Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Therapeutic cell engineering with surface-conjugated synthetic nanoparticles

Abstract

A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug–loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stable conjugation of nanoparticles (NPs) to the surfaces of T cells and HSCs via cell-surface thiols.
Figure 2: Nanoparticle conjugation does not affect key T cell functions.
Figure 3: Nanoparticle-decorated T cells efficiently carry surface-tethered nanoparticles into antigen-expressing tumors.
Figure 4: Pmel-1 T cells conjugated with IL-15Sa– and IL-21–releasing nanoparticles robustly proliferate in vivo and eradicate established B16 melanomas.
Figure 5: HSCs carrying GSK-3β inhibitor–loaded nanoparticles reconstitute recipient animals with rapid kinetics after bone marrow transplants without affecting multilineage differentiation potential.

Similar content being viewed by others

References

  1. Fiorina, P., Shapiro, A.M., Ricordi, C. & Secchi, A. The clinical impact of islet transplantation. Am. J. Transplant. 8, 1990–1997 (2008).

    Article  CAS  Google Scholar 

  2. Alison, M.R., Islam, S. & Lim, S.M. Cell therapy for liver disease. Curr. Opin. Mol. Ther. 11, 364–374 (2009).

    CAS  PubMed  Google Scholar 

  3. Alper, J. Geron gets green light for human trial of ES cell–derived product. Nat. Biotechnol. 27, 213–214 (2009).

    Article  CAS  Google Scholar 

  4. Dimos, J.T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons 321, 1218–1221 (2008).

  5. Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    Article  CAS  Google Scholar 

  6. Hunder, N.N. et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).

    Article  CAS  Google Scholar 

  7. Mackinnon, S., Thomson, K., Verfuerth, S., Peggs, K. & Lowdell, M. Adoptive cellular therapy for cytomegalovirus infection following allogeneic stem cell transplantation using virus-specific T cells. Blood Cells Mol. Dis. 40, 63–67 (2008).

    Article  CAS  Google Scholar 

  8. Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139–148 (2005).

    Article  CAS  Google Scholar 

  9. Wallace, A. et al. Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T cell therapy of established solid cancers. Clin. Cancer Res. 14, 3966–3974 (2008).

    Article  CAS  Google Scholar 

  10. Trowbridge, J.J., Xenocostas, A., Moon, R.T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat. Med. 12, 89–98 (2006).

    Article  CAS  Google Scholar 

  11. Berger, C. et al. Safety and immunological effects of IL-15 administration in nonhuman primates. Blood 114, 2417–2426 (2009).

    Article  CAS  Google Scholar 

  12. Thompson, J.A. et al. Recombinant interleukin 2 toxicity, pharmacokinetics and immunomodulatory effects in a phase I trial. Cancer Res. 47, 4202–4207 (1987).

    CAS  PubMed  Google Scholar 

  13. Treisman, J. et al. Interleukin-2–transduced lymphocytes grow in an autocrine fashion and remain responsive to antigen. Blood 85, 139–145 (1995).

    CAS  PubMed  Google Scholar 

  14. Sahaf, B., Heydari, K., Herzenberg, L.A. & Herzenberg, L.A. Lymphocyte surface thiol levels. Proc. Natl. Acad. Sci. USA 100, 4001–4005 (2003).

    Article  CAS  Google Scholar 

  15. Bernstein, I.D., Boyd, R.L. & van den Brink, M.R. Clinical strategies to enhance posttransplant immune reconstitution. Biol. Blood Marrow Transplant. 14, 94–99 (2008).

    Article  Google Scholar 

  16. Jain, R.K. A new target for tumor therapy. N. Engl. J. Med. 360, 2669–2671 (2009).

    Article  CAS  Google Scholar 

  17. Overwijk, W.W. et al. gp100/pmel 17 is a murine tumor rejection antigen: induction of 'self'-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J. Exp. Med. 188, 277–286 (1998).

    Article  CAS  Google Scholar 

  18. Rubinstein, M.P. et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα. Proc. Natl. Acad. Sci. USA 103, 9166–9171 (2006).

    Article  CAS  Google Scholar 

  19. Lu, J. et al. Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes. Clin. Cancer Res. 8, 3877–3884 (2002).

    CAS  PubMed  Google Scholar 

  20. Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808–813 (2009).

    Article  CAS  Google Scholar 

  21. Dinauer, N. et al. Selective targeting of antibody-conjugated nanoparticles to leukemic cells and primary T lymphocytes. Biomaterials 26, 5898–5906 (2005).

    Article  CAS  Google Scholar 

  22. Davis, M.E., Chen, Z.G. & Shin, D.M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7, 771–782 (2008).

    Article  CAS  Google Scholar 

  23. Prescher, J.A., Dube, D.H. & Bertozzi, C.R. Chemical remodelling of cell surfaces in living animals. Nature 430, 873–877 (2004).

    Article  CAS  Google Scholar 

  24. Reddy, S.T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 25, 1159–1164 (2007).

    Article  CAS  Google Scholar 

  25. Woodrow, K.A. et al. Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nat. Mater. 8, 526–533 (2009).

    Article  CAS  Google Scholar 

  26. Bin Na, H., Song, I.C. & Hyeon, T. Inorganic nanoparticles for MRI contrast agents. Adv. Mater. 21, 2133–2148 (2009).

    Article  Google Scholar 

  27. Tong, R. et al. Nanopolymeric therapeutics. MRS Bull. 34, 422–431 (2009).

    Article  CAS  Google Scholar 

  28. Bartlett, D.W., Su, H., Hildebrandt, I.J., Weber, W.A. & Davis, M.E. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl. Acad. Sci. USA 104, 15549–15554 (2007).

    Article  CAS  Google Scholar 

  29. Weissleder, R., Kelly, K., Sun, E.Y., Shtatland, T. & Josephson, L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nat. Biotechnol. 23, 1418–1423 (2005).

    Article  CAS  Google Scholar 

  30. Dhar, S., Gu, F.X., Langer, R., Farokhzad, O.C. & Lippard, S.J. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc. Natl. Acad. Sci. USA 105, 17356–17361 (2008).

    Article  CAS  Google Scholar 

  31. Kirpotin, D.B. et al. Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res. 66, 6732–6740 (2006).

    Article  CAS  Google Scholar 

  32. Reichardt, W. et al. Impact of mammalian target of rapamycin inhibition on lymphoid homing and tolerogenic function of nanoparticle-labeled dendritic cells following allogeneic hematopoietic cell transplantation. J. Immunol. 181, 4770–4779 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the US National Institutes of Health (CA140476), the US National Science Foundation (Materials Research Science and Engineering Center award DMR-02-13282), Cancer Center Support (core) grant P30-CA14051 from the US National Cancer Institute and a gift to the Koch Institute by Curtis and Cathy Marble. D.J.I. is an investigator of the Howard Hughes Medical Institute. We thank M. Sadelain (Memorial Sloan-Kettering Cancer Center) for extG-luc and M. van den Brink (Memorial Sloan-Kettering Cancer Center) for F-luc–transgenic mice.

Author information

Authors and Affiliations

Authors

Contributions

M.T.S. designed and conducted all experiments and wrote the manuscript. J.J.M. assisted in T cell transmigration assays, optimization of multilamellar lipid nanoparticle synthesis and in vivo nanoparticle biodistribution assays. S.H.U. assisted optimization of multilamellar lipid nanoparticle synthesis. A.B. assisted in initial in vitro T cell assays, collected electron microscopy images and contributed experimental suggestions. D.J.I. supervised all experiments and wrote the manuscript.

Corresponding author

Correspondence to Darrell J Irvine.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–17 and Supplementary Methods (PDF 4409 kb)

Supplementary Movie 1

Maleimide-bearing NPs are not internalized after cell surface conjugation. CD8+ T cells were surface-conjugated with fluorescent DiD-tagged NPs (Fig. 1c). Sequences of single confocal z-sections acquired at 0.4 1m intervals throughout the T cells are shown here and in Supplementary Movie 2. (MOV 642 kb)

Supplementary Movie 2

Maleimide-bearing NPs are not internalized after cell surface conjugation. CD8+ T cells were surface-conjugated with fluorescent DiD-tagged NPs (Fig. 1c). Sequences of single confocal z-sections acquired at 0.4 1m intervals throughout the T cells are here and in Supplementary Movie 1. (MOV 713 kb)

Supplementary Movie 3

Membrane-tethered NPs are retained on the cell surface of tumor homing T lymphocytes. Explanted cross-sectioned EG7-OVA tumors 2 d after T cell injection (Fig 3c). CellTracker green–labeled OT-1 T cells and rhodamine lipid–coated NPs (magenta) were visualized by confocal microscopy. Sequences of single confocal z-sections acquired at 0.4-1m intervals throughout the T cells are shown here and in Supplementary Movie 4. Scale bar, 1.5 1m. (MOV 670 kb)

Supplementary Movie 4

Membrane-tethered NPs are retained on the cell surface of tumor homing T lymphocytes. Explanted cross-sectioned EG7-OVA tumors 2 d after T cell injection (Fig 3c). CellTracker green–labeled OT-1 T cells and rhodamine lipid–coated NPs (magenta) were visualized by confocal microscopy. Sequences of single confocal z-sections acquired at 0.4-1m intervals throughout the T cells are shown here and in Supplementary Movie 3. Scale bar, 1.5 1m. (MOV 1140 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stephan, M., Moon, J., Um, S. et al. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med 16, 1035–1041 (2010). https://doi.org/10.1038/nm.2198

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2198

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer